Oxo-oxazoline derivatives are critical intermediates for compounds (WO98/08867) which are TRH (thyrotropin releasing hormone) derivatives represented by the following general formula (VIII): wherein RA is a hydrogen atom or optionally substituted lower alkyl: Y is an optionally substituted alkyl.
Further, compounds represented by the following general formulas (III-A), (III-B), (IV-A), or (IV-B): wherein R1 is an optionally substituted lower alkyl, an optionally substituted aryl, an alkynyl, or an optionally substituted heteroaryl, and derivatives thereof, are useful as tools for combinatorial chemistry.
Conventionally, as a method for producing oxo-oxazoline derivatives having a lower alkyloxycarbonyl group or a carboxyl group, a method of cyclizing a starting material while retaining its stereochemistry, and a method using cyclization reaction without reference to stereoselectivity are known.
An example of the method of cyclizing a starting material while retaining its stereochemistry is the following: (Tetrahedron, 48, 2507, 1992). In this reaction, L-allo-threonine used as a starting material is allowed to react with phosgene and potassium hydroxide in toluene at 0° C. for one hour, thereby obtaining a cyclized product which retains its stereochemisty. Unfortunately, this method encounters a problem in industrialization since the method employs L-allo-threonine which is more expensive than its natural type, and phosgene which is toxic to the human body.
An example of the cyclization method without reference to stereoselectivity is the following: (Japanese Laid-Open Publication No. 60-34955). In this reaction, a starting material is allowed to react with potassium carbonate in water at 60° C. for 1.5 hours to obtain a cyclized product. It is believed that the stereochemistry of the material is maintained in view of the mechanism of this method. Therefore, it is considered that allo-threonine needs to be used as a starting material in order to obtain a cis-form cyclized product.
Although a resultant cyclized product is an oxo-oxazoline derivative which does not have a lower alkyloxycarbonyl group or a carboxyl group, the following method is known: (Bull. Chem. Soc. Japan., 44, 2515, 1971). In this reaction, a starting material is allowed to react in thionyl chloride at 60° C. for 24 hours without solvent, thereby obtaining a cyclized product at a yield of 65%. In this method, similar to the method of the present invention, the position of an ethyl group is inverted after the reaction. However, the starting material is not an amino acid derivative, and the relationship between the amino group and the hydroxyl group of the starting material is different from that of a starting material used in the method of the present invention. Moreover, since the reaction is conducted in thionyl chloride, the yield is as low as 65%.
Similar to the method of the present invention, a cyclization reaction with inversion is known: (Heterocycl. Commun., 2, 55, 1996). An example in which trifluoroacetic anydride is used in the first step is disclosed. Although in the method of the present invention, the yield of a cyclization reaction is as high as 83%, the yield of the cyclization reaction disclosed in the above-described publication is as low as 40% in both a method using tosyl chloride and a method using trifluoroacetic anydride. Moreover, the method of the present invention is superior in regard to simplicity of reaction.